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Introduction: Persons living with HIV (PLWH) experience the early onset of age-related illnesses, even in the setting of successful human immunodeficiency virus (HIV) suppression with highly active antiretroviral therapy (HAART). HIV infection is associated with accelerated epigenetic aging as measured using DNA methylation (DNAm)-based estimates of biological age and of telomere length (TL). Methods: DNAm levels (Infinium MethylationEPIC BeadChip) from peripheral blood mononuclear cells from 200 PLWH and 199 HIV-seronegative (SN) participants matched on chronologic age, hepatitis C virus, and time intervals were used to calculate epigenetic age acceleration, expressed as age-adjusted acceleration residuals from 4 epigenetic clocks [Horvath's pan-tissue age acceleration residual (AAR), extrinsic epigenetic age acceleration (EEAA), phenotypic epigenetic age acceleration (PEAA), and grim epigenetic age acceleration (GEAA)] plus age-adjusted DNAm-based TL (aaDNAmTL). Epigenetic age acceleration was compared for PLWH and SN participants at two visits: up to 1.5 years prior and 2-3 years after HAART (or equivalent visits). Flow cytometry was performed in PLWH and SN participants at both visits to evaluate T-cell subsets. Results: Epigenetic age acceleration in PLWH decreased after the initiation of HAART but remained greater post-HAART than that in age-matched SN participants, with differences in medians of 6.6, 9.1, and 7.7 years for AAR, EEAA, and PEAA, respectively, and 0.39 units of aaDNAmTL shortening (all p < 0.001). Cumulative HIV viral load after HAART initiation was associated with some epigenetic acceleration (EEAA, PEAA, and aaDNAmTL), but even PLWH with undetectable HIV post-HAART showed persistent epigenetic age acceleration compared to SN participants (p < 0.001). AAR, EEAA, and aaDNAmTL showed significant associations with total, naïve, and senescent CD8 T-cell counts; the total CD4 T-cell counts were associated with AAR, EEAA, and PEAA (p = 0.04 to <0.001). In an epigenome-wide analysis using weighted gene co-methylation network analyses, 11 modules demonstrated significant DNAm differences pre- to post-HAART initiation. Of these, nine were previously identified as significantly different from pre- to post-HIV infection but in the opposite direction. Discussion: In this large longitudinal study, we demonstrated that, although the magnitude of the difference decreases with HAART is associated with the cumulative viral load, PLWH are persistently epigenetically older than age-matched SN participants even after the successful initiation of HAART, and these changes are associated with changes in T-cell subsets.
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Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2-3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10-7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.
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PURPOSE: COVID-19 continues to affect millions of individuals worldwide, both in the short and long term. The post-acute complications of SARS-CoV-2 infection, referred to as long COVID, result in diverse symptoms affecting multiple organ systems. Little is known regarding how the symptoms associated with long COVID progress and resolve over time. The Johns Hopkins COVID Long Study aims to prospectively examine the short-term and long-term consequences of COVID-19 in individuals both with and without a history of SARS-CoV-2 infection using self-reported data collected in an online survey. PARTICIPANTS: 16 764 adults with a history of SARS-CoV-2 infection and 799 adults without a history of SARS-CoV-2 infection who completed an online baseline survey. FINDINGS TO DATE: This cohort profile describes the baseline characteristics of the Johns Hopkins COVID Long Study. Among 16 764 participants with a history of SARS-CoV-2 infection and defined long COVID status, 75% reported a very good or excellent health status prior to infection, 99% reported experiencing at least one COVID-19 symptom during the acute phase of infection, 9.9% reported hospitalisation and 63% were defined as having long COVID using the WHO definition. FUTURE PLANS: Analysis of longitudinal data will be used to investigate the progression and resolution of long COVID symptoms over time.
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COVID-19 , Síndrome Post Agudo de COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiología , Femenino , Masculino , Estudios Prospectivos , Persona de Mediana Edad , Adulto , Estados Unidos/epidemiología , Anciano , Hospitalización/estadística & datos numéricos , Adulto Joven , Autoinforme , Estado de SaludRESUMEN
Genetic studies of non-traditional glycemic biomarkers, glycated albumin and fructosamine, can shed light on unknown aspects of type 2 diabetes genetics and biology. We performed a multi-phenotype GWAS of glycated albumin and fructosamine from 7,395 White and 2,016 Black participants in the Atherosclerosis Risk in Communities (ARIC) study on common variants from genotyped/imputed data. We discovered 2 genome-wide significant loci, one mapping to known type 2 diabetes gene (ARAP1/STARD10) and another mapping to a novel region (UGT1A complex of genes) using multi-omics gene-mapping strategies in diabetes-relevant tissues. We identified additional loci that were ancestry- and sex-specific (e.g., PRKCA in African ancestry, FCGRT in European ancestry, TEX29 in males). Further, we implemented multi-phenotype gene-burden tests on whole-exome sequence data from 6,590 White and 2,309 Black ARIC participants. Ten variant sets annotated to genes across different variant aggregation strategies were exome-wide significant only in multi-ancestry analysis, of which CD1D, EGFL7/AGPAT2 and MIR126 had notable enrichment of rare predicted loss of function variants in African ancestry despite smaller sample sizes. Overall, 8 out of 14 discovered loci and genes were implicated to influence these biomarkers via glycemic pathways, and most of them were not previously implicated in studies of type 2 diabetes. This study illustrates improved locus discovery and potential effector gene discovery by leveraging joint patterns of related biomarkers across the entire allele frequency spectrum in multi-ancestry analysis. Future investigation of the loci and genes potentially acting through glycemic pathways may help us better understand risk of developing type 2 diabetes.
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PROBLEM: Bacterial vaginosis (BV) disproportionally impacts Black and Hispanic women, placing them at risk for HIV, sexually transmitted infections and preterm birth. It is unknown whether there are differences by genetic ancestry in BV risk or whether polymorphisms associated with BV risk differ by ancestry. METHODS: Women's Interagency HIV Study (WIHS) participants with longitudinal Nugent scores were dichotomized as having (n = 319, Nugent 7-10) or not having BV (n = 367, Nugent 0-3). Genetic ancestry was defined by clustering of principal components from ancestry informative markers and further stratified by BV status. 627 single nucleotide polymorphisms (SNPs) across 41 genes important in mucosal defense were identified in the WIHS GWAS. A logistic regression analysis was adjusted for nongenetic predictors of BV and self-reported race/ethnicity to assess associations between genetic ancestry and genotype. RESULTS: Self-reported race and genetic ancestry were associated with BV risk after adjustment for behavioral factors. Polymorphisms in mucosal defense genes including syndecans, cytokines and toll-like receptors (TLRs) were associated with BV in all ancestral groups. CONCLUSIONS: The common association of syndecan, cytokine and TLR genes and the importance of immune function and inflammatory pathways in BV, suggests these should be targeted for further research on BV pathogenesis and therapeutics.
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Infecciones por VIH , Polimorfismo de Nucleótido Simple , Vaginosis Bacteriana , Humanos , Femenino , Vaginosis Bacteriana/genética , Adulto , Infecciones por VIH/genética , Predisposición Genética a la Enfermedad , Citocinas/genética , Factores de Riesgo , Estudio de Asociación del Genoma Completo , Receptores Toll-Like/genéticaRESUMEN
Purpose: COVID-19 disease continues to affect millions of individuals worldwide, both in the short and long term. The post-acute complications of SARS-CoV-2 infection, referred to as long COVID, result in diverse symptoms affecting multiple organ systems. Little is known regarding how the symptoms associated with long COVID progress and resolve over time. The Johns Hopkins COVID Long Study aims to prospectively examine the short- and long-term consequences of COVID-19 disease in individuals both with and without a history of SARS-CoV-2 infection using self-reported data collected in an online survey. Participants: Sixteen thousand, seven hundred sixty-four adults with a history of SARS-CoV-2 infection and 799 adults without a history of SARS-CoV-2 infection who completed an online baseline survey. Findings to date: This cohort profile describes the baseline characteristics of the Johns Hopkins COVID Long Study. Among 16,764 participants with a history of SARS-CoV-2 infection and defined long COVID status, 75% reported a good or excellent health status prior to infection, 99% reported experiencing at least one COVID-19 symptom during the acute phase of infection, 9.9% reported a hospitalization, and 63% were defined as having long COVID using the WHO definition. Future plans: Analysis of longitudinal data will be used to investigate the progression and resolution of long COVID symptoms over time.
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Nearly 300 million individuals live with chronic hepatitis B virus (HBV) infection (CHB), for which no curative therapy is available. As viral diversity is associated with pathogenesis and immunological control of infection, improved methods to characterize this diversity could aid drug development efforts. Conventionally, viral sequencing data are mapped/aligned to a reference genome, and only the aligned sequences are retained for analysis. Thus, reference selection is critical, yet selecting the most representative reference a priori remains difficult. We investigate an alternative pangenome approach which can combine multiple reference sequences into a graph which can be used during alignment. Using simulated short-read sequencing data generated from publicly available HBV genomes and real sequencing data from an individual living with CHB, we demonstrate alignment to a phylogenetically representative 'genome graph' can improve alignment, avoid issues of reference ambiguity, and facilitate the construction of sample-specific consensus sequences more genetically similar to the individual's infection. Graph-based methods can, therefore, improve efforts to characterize the genetics of viral pathogens, including HBV, and have broader implications in host-pathogen research.
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Secuencia de Consenso , Genoma Viral , Virus de la Hepatitis B , Virus de la Hepatitis B/genética , Humanos , Secuencia de Consenso/genética , Filogenia , Alineación de Secuencia/métodos , Variación Genética , Hepatitis B Crónica/virología , ADN Viral/genética , Análisis de Secuencia de ADN/métodosRESUMEN
Background: Astroviral infections commonly cause acute nonbacterial gastroenteritis in children globally. However, these infections often go undiagnosed outside of research settings. There is no treatment available for astrovirus, and Astroviridae strain diversity presents a challenge to potential vaccine development. Methods: To address our hypothesis that host genetic risk factors are associated with astrovirus disease susceptibility, we performed a genome-wide association study of astrovirus infection in the first year of life from children enrolled in 2 Bangladeshi birth cohorts. Results: We identified a novel region on chromosome 1 near the loricrin gene (LOR) associated with astrovirus diarrheal infection (rs75437404; meta-analysis P = 8.82 × 10-9; A allele odds ratio, 2.71) and on chromosome 10 near the prolactin releasing hormone receptor gene (PRLHR) (rs75935441; meta-analysis P = 1.33 × 10-8; C allele odds ratio, 4.17). The prolactin-releasing peptide has been shown to influence feeding patterns and energy balance in mice. In addition, several single-nucleotide polymorphisms in the chromosome 1 locus have previously been associated with expression of innate immune system genes PGLYRP4, S100A9, and S100A12. Conclusions: This study identified 2 significant host genetic regions that may influence astrovirus diarrhea susceptibility and should be considered in further studies.
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BACKGROUND: Persistent symptoms after severe acute respiratory disease coronavirus 2 (SARS-COV-2; long COVID) occur in 10%-55% of individuals, but the impact on daily functioning and disability remains unquantified. METHODS: To characterize disability associated with long COVID, we analyzed baseline data from an online, US-based cohort study. Adult participants included those reporting a history of COVID-19 (n = 8874) or never having COVID-19 (n = 633) without prior disability. The main outcomes were self-reported physical mobility, instrumental activities of daily living (IADL), and mental fatigue disability, assessed by measuring 5 disability components: difficulty walking a quarter mile or climbing 10 stairs (mobility), difficulty doing light or heavy housework (IADL), and Wood Mental Fatigue Inventory score (mental fatigue). RESULTS: Of 7926 participants with long COVID, 65% were classified with at least one disability, as compared with 6% and 14% for resolved COVID and no COVID, respectively. Additionally, 22% were classified as disabled in all 3 categories. Age, prior comorbidity, increased body mass index, female sex, COVID-19 hospitalization, non-white/multi-race were associated with higher disability burden. Dizziness and heavy limbs at infection were associated with disability regardless of hospitalization. Dyspnea and tremors were associated with disability in non-hospitalized individuals. Vaccination was protective against disability. CONCLUSIONS: We observed a high burden of new disability associated with long COVID, which has serious implications for individual and societal health. Longitudinal evaluation of COVID-19 patients is necessary to identify patterns of recovery and treatment options.
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Glycated hemoglobin, fasting glucose, glycated albumin, and fructosamine are biomarkers that reflect different aspects of the glycemic process. Genetic studies of these glycemic biomarkers can shed light on unknown aspects of type 2 diabetes genetics and biology. While there exists several GWAS of glycated hemoglobin and fasting glucose, very few GWAS have focused on glycated albumin or fructosamine. We performed a multi-phenotype GWAS of glycated albumin and fructosamine from 7,395 White and 2,016 Black participants in the Atherosclerosis Risk in Communities (ARIC) study on the common variants from genotyped/imputed data. We found 2 genome-wide significant loci, one mapping to known type 2 diabetes gene (ARAP1/STARD10, p = 2.8 × 10-8) and another mapping to a novel gene (UGT1A, p = 1.4 × 10-8) using multi-omics gene mapping strategies in diabetes-relevant tissues. We identified additional loci that were ancestry-specific (e.g., PRKCA from African ancestry individuals, p = 1.7 × 10-8) and sex-specific (TEX29 locus in males only, p = 3.0 × 10-8). Further, we implemented multi-phenotype gene-burden tests on whole-exome sequence data from 6,590 White and 2,309 Black ARIC participants. Eleven genes across different rare variant aggregation strategies were exome-wide significant only in multi-ancestry analysis. Four out of 11 genes had notable enrichment of rare predicted loss of function variants in African ancestry participants despite smaller sample size. Overall, 8 out of 15 loci/genes were implicated to influence these biomarkers via glycemic pathways. This study illustrates improved locus discovery and potential effector gene discovery by leveraging joint patterns of related biomarkers across entire allele frequency spectrum in multi-ancestry analyses. Most of the loci/genes we identified have not been previously implicated in studies of type 2 diabetes, and future investigation of the loci/genes potentially acting through glycemic pathways may help us better understand risk of developing type 2 diabetes.
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Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individuals DPB1*04:01 was associated with higher HBV antibody responses (p=4.5×10-30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen 'a-determinant' segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion.
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[This corrects the article DOI: 10.1016/j.isci.2022.104488.].
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Medical and population health science researchers frequently make ambiguous statements about whether they believe their study sample or results are representative of some (implicit or explicit) target population. This article provides a comprehensive definition of representativeness, with the goal of capturing the different ways in which a study can be representative of a target population. It is proposed that a study is representative if the estimate obtained in the study sample is generalisable to the target population (owing to representative sampling, estimation of stratum specific effects, or quantitative methods to generalise or transport estimates) or the interpretation of the results is generalisable to the target population (based on fundamental scientific premises and substantive background knowledge). This definition is explored in the context of four covid-19 studies, ranging from laboratory science to descriptive epidemiology. All statements regarding representativeness should make clear the way in which the study results generalise, the target population the results are being generalised to, and the assumptions that must hold for that generalisation to be scientifically or statistically justifiable.
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Biological sex and host genetics influence HIV pathogenesis. Females have a higher likelihood of spontaneous viral control and lower set point viral load (spVL). No prior studies have assessed sex-specific genetics of HIV. To address this, we performed a sex-stratified genome-wide association study using data from the ICGH. Although it is the largest collection of genomic data in HIV, this multiethnic sample of 9,705 people is 81.3% male. We sought to identify sex-specific genetic variants and genes associated with HIV spVL and control. We confirmed associations in the HLA and CCR5 regions in males and HLA in females. Gene-based analyses detected associations between HIV spVL and PET100, PCP2, XAB2, and STXBP2 only in males. We detected variants with a significant sex-differential effect on spVL in SDC3 and PUM1 (rs10914268) and PSORS1C2 (rs1265159) and on HIV control in SUB1 (rs687659), AL158151.3, PTPA, and IER5L (rs4387067). Those variants have epigenetic and genetic interactions with relevant genes with both cis and trans effects. In summary, we identified sex-shared associations at the single-variant level, sex-specific associations at the gene-based level, and genetic variants with significant differential effects between the sexes.
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Infecciones por VIH , VIH-1 , Femenino , Humanos , Masculino , Infecciones por VIH/genética , VIH-1/genética , Carga Viral/genética , Estudio de Asociación del Genoma Completo , Genómica , Proteínas de Unión al ARN/genéticaRESUMEN
BACKGROUND: Diarrhea is the second leading cause of death in children under 5 years old worldwide. Known diarrhea risk factors include sanitation, water sources, and pathogens but do not fully explain the heterogeneity in frequency and duration of diarrhea in young children. We evaluated the role of host genetics in diarrhea. METHODS: Using 3 well-characterized birth cohorts from an impoverished area of Dhaka, Bangladesh, we compared infants with no diarrhea in the first year of life to those with an abundance, measured by either frequency or duration. We performed a genome-wide association analysis for each cohort under an additive model and then meta-analyzed across the studies. RESULTS: For diarrhea frequency, we identified 2 genome-wide significant loci associated with not having any diarrhea, on chromosome 21 within the noncoding RNA AP000959 (C allele odds ratio [OR] = 0.31, P = 4.01 × 10-8), and on chromosome 8 within SAMD12 (T allele OR = 0.35, P = 4.74 × 10-7). For duration of diarrhea, we identified 2 loci associated with no diarrhea, including the same locus on chromosome 21 (C allele OR = 0.31, P = 1.59 × 10-8) and another locus on chromosome 17 near WSCD1 (C allele OR = 0.35, P = 1.09 × 10-7). CONCLUSIONS: These loci are in or near genes involved in enteric nervous system development and intestinal inflammation and may be potential targets for diarrhea therapeutics.
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Diarrea , Estudio de Asociación del Genoma Completo , Niño , Humanos , Lactante , Preescolar , Bangladesh/epidemiología , Factores de Riesgo , Diarrea/epidemiología , Diarrea/genética , AlelosRESUMEN
BACKGROUND: Cryptosporidium spp. are responsible for significant diarrheal morbidity and mortality in under-5 children. There is no vaccine; thus, a focus on prevention is paramount. Prior studies suggest that person-to-person spread may be an important pathway for transmission to young children. Here we describe a longitudinal cohort study of 100 families with infants to determine rates of cryptosporidiosis within households during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Families living in Mirpur, Bangladesh, with 1 infant aged 6-8 months were enrolled and followed with weekly illness survey and stool testing for Cryptosporidium for 8 months. RESULTS: From December 2020 to August 2021, 100 families were enrolled. Forty-four percent of index children and 35% of siblings had at least 1 Cryptosporidium infection. Shedding of Cryptosporidium occurred for a mean (standard deviation) of 19 (8.3) days in index infants, 16.1 (11.6) days in children 1-5 years, and 16.2 (12.8) days in adults. A longer duration of Cryptosporidium shedding was associated with growth faltering in infants. There was a spike in Cryptosporidium cases in May 2021, which coincided with a spike in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases in the region. CONCLUSIONS: In this intensive, longitudinal study of Cryptosporidium infection in families we found high rates of cryptosporidiosis in infants and children, and prolonged parasite shedding, especially among malnourished children. These data support that transmission within the household is an important route of exposure for young infants and that treatment of nondiarrheal infection to interrupt person-to-person transmission within the home may be essential for preventing cryptosporidiosis in infants.
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COVID-19 , Criptosporidiosis , Cryptosporidium , Niño , Adulto , Lactante , Humanos , Preescolar , Criptosporidiosis/epidemiología , Criptosporidiosis/complicaciones , Estudios Longitudinales , Estudios Prospectivos , COVID-19/epidemiología , COVID-19/complicaciones , SARS-CoV-2 , Estudios de Cohortes , Diarrea/parasitología , Heces/parasitologíaRESUMEN
Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures.
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Enfermedades Transmisibles , Hepatitis C , Humanos , Estudio de Asociación del Genoma Completo , Enfermedades Transmisibles/genética , Fenotipo , Hepatitis C/genética , HepacivirusRESUMEN
Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.
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Miopía , Errores de Refracción , Humanos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Miopía/genética , Errores de Refracción/genética , Población Blanca , Pueblos del Este de AsiaRESUMEN
Hepatitis B virus (HBV) remains a global public health concern, with over 250 million individuals living with chronic HBV infection (CHB) and no curative therapy currently available. Viral diversity is associated with CHB pathogenesis and immunological control of infection. Improved methods to characterize the viral genome at both the population and intra-host level could aid drug development efforts. Conventionally, HBV sequencing data are aligned to a linear reference genome and only sequences capable of aligning to the reference are captured for analysis. Reference selection has additional consequences, including sample-specific 'consensus' sequence construction. It remains unclear how to select a reference from available sequences and whether a single reference is sufficient for genetic analyses. Using simulated short-read sequencing data generated from full-length publicly available HBV genome sequences and HBV sequencing data from a longitudinally sampled individual with CHB, we investigate alternative graph-based alignment approaches. We demonstrate that using a phylogenetically representative 'genome graph' for alignment, rather than linear reference sequences, avoids issues of reference ambiguity, improves alignment, and facilitates the construction of sample-specific consensus sequences genetically similar to an individual's infection. Graph-based methods can therefore improve efforts to characterize the genetics of viral pathogens, including HBV, and may have broad implications in host pathogen research.